Primary Immunodeficiencies - From genetic basis to therapeutic targets


General Background
In this project, we aim to decode the genetic and immunological factors characterizing unsolved immunodeficiencies of innate immune system, to obtain a comprehensive picture of the pathways that are involved for host defense against specific microorganisms, and with the ultimate goal to design novel immunotherapeutic strategies.

Objective
    The overall aim of this proposal is to revolutionize the disease gene identification and in-depth functional understanding of Mendelian immunodeficiencies by combining a genome-first approach with targeted functional follow-up assays, accompanied with a systematic drug screen to explore therapeutic options.
    In order to reach these goals we will follow a 4-step approach:
  • select patients (sporadic and families) with severe unexplained Mendelian forms of immunodeficiencies in the innate immune system
  • use exome sequencing and bioinformatic prioritization of causative variants to identify novel immunodeficiency genes
  • accompany whole exome sequencing results with functional follow-up including RNA sequencing of stimulated and un-stimulated patient cell lines
  • explore new treatment options for patients with disorders of innate immunity based on the genetic and functional studies

Project description
Evolution has provided humans with an immune system comprised of an advanced interrelated network of cells and bioactive molecules, finely tuned to provide defense against microorganisms (bacteria, fungi, viruses), while avoiding organ self-damage. However, its complexity makes the human immune system vulnerable to genetic variation and errors, which can result in loss-of-function defects and immunodeficiencies with an enhanced susceptibility to infection, or gain-of-function errors accompanied by autoimmune and autoinflammatory diseases.
In this project, we aim to decode the genetic and immunological factors characterizing unsolved immunodeficiencies of innate immune system, to obtain a comprehensive picture of the pathways that are involved for host defense against specific microorganisms, and with the ultimate goal to design novel immunotherapeutic strategies.
We will: 1.) elucidate the genetic cause of 50 well described cases with rare Mendelian immunodeficiency syndromes by using a family-based exome sequencing approach. Data interpretation will be greatly facilitated by integrating knowledge obtained from functional assays performed for each individual patient 2.) we will further study the dysregulated biological pathways by RNA sequencing of in vitro stimulated patient cell lines; and 3.) we will leverage the pathophysiological knowledge on the affected pathways to explore immunotherapeutic options with available compounds on patient cell lines.
The research on immunodeficiency disorders offers a great advantage compared to e.g. developmental diseases, as the affected tissue can be accessed directly by drawing blood. While DNA and RNA can be studied directly to validate identified mutations, and show their consequences on RNA level, an additional advantage is that the functional consequences of genetic defects (i.e. defects in cytokine production or pathogen recognition) can be monitored in vitro using patient cells. These studies will not only allow us to obtain insights in the specific pathology of these patients, provide leads to new therapies and offer better counseling, but also provide a more complete picture of how the human host deals with the various microbes and how the inflammatory response is regulated. Thus, these studies on experiments of nature have relevance also to other fields of biomedical science (e.g., vascular biology, diabetology, neurobiology), where there is a fast growing interest in the inflammatory response.

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